1Y8D

Dimeric parallel-stranded tetraplex with 3+1 5' G-tetrad interface, single-residue chain reversal loops and GAG triad in the context of A(GGGG) pentad

Summary for 1Y8D

• Entry DOI: 10.2210/pdb1y8d/pdb
• Related: 1EEG 1JJP
• Descriptor: 5'-D(*GP*GP*GP*GP*TP*GP*GP*GP*AP*GP*GP*AP*GP*GP*GP*T)-3' (1 entity in total)
• Functional Keywords: dimeric parallel-stranded quadruplex; dna aptamer;hiv-1 integrase inhibitor design; 3+1 g-tetrad; single nucleotide chain reversal loop; gag triad; (a)gggg pentad, dna
• Total number of polymer chains: 2
• Total formula weight: 10280.62

Authors

Phan, A.T.,Kuryavyi, V.V.,Ma, J.-B.,Faure, A.,Andreola, M.-L.,Patel, D.J. (deposition date: 2004-12-11, release date: 2005-02-01, Last modification date: 2024-05-22)

Primary citation

Phan, A.T.,Kuryavyi, V.V.,Ma, J.-B.,Faure, A.,Andreola, M.-L.,Patel, D.J.
An interlocked dimeric parallel-stranded DNA quadruplex: A potent inhibitor of HIV-1 integrase
Proc.Natl.Acad.Sci.USA, 102:634-639, 2005

PubMed Abstract: We report on the NMR-based solution structure of the 93del d(GGGGTGGGAGGAGGGT) aptamer, a potent nanomolar inhibitor of HIV-1 integrase. This guanine-rich DNA sequence adopts an unusually stable dimeric quadruplex architecture in K+ solution. Within each 16-nt monomer subunit, which contains one A.(G.G.G.G) pentad sandwiched between two G.G.G.G tetrads, all G-stretches are parallel, and all guanines are anti with the exception of G1, which is syn. Dimer formation is achieved through mutual pairing of G1 of one monomer, with G2, G6, and G13 of the other monomer, to complete G.G.G.G tetrad formation. There are three single-nucleotide double-chain-reversal loops within each monomer fold, such that the first (T5) and third (A12) loops bridge three G-tetrad layers, whereas the second (A9) loop bridges two G-tetrad layers and participates in A.(G.G.G.G) pentad formation. Results of NMR and of integrase inhibition assays on loop-modified sequences allowed us to propose a strategy toward the potential design of improved HIV-1 integrase inhibitors. Finally, we propose a model, based on molecular docking approaches, for positioning the 93del dimeric DNA quadruplex within a basic channel/canyon formed between subunits of a dimer of dimers of HIV-1 integrase.

PubMed: 15637158
DOI: 10.1073/pnas.0406278102

Experimental method

SOLUTION NMR